Every year, cardiovascular and cerebrovascular diseases such as cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease and arteriosclerosis take nearly 12 million lives, which are close to ¼ of the total death toll in the world, and become the number one enemy of human health. The number of people dying from cardiovascular disease in China each year is more than 2.6 million, and 75% of surviving patients are disabled, and more than 40% of them are severely disabled. The problem of thrombosis caused by cardiovascular and cerebrovascular diseases and diabetes and complications thereof has become an urgent problem to be solved today.
According to Datamonitor 2011 data from independent market analysts, with the production of generic drugs, the share of cardiovascular and metabolic diseases in the seven major markets will peak in 2011 and then gradually decrease. The sales will decrease from $109 billion in 2010 to $101 billion in 2019. The thrombus market remained basically stable, from $19.5 billion in 2010 to $18.9 billion in 2019 (Datamonitor: HC00034-001, HC00139-001). Guangzhou Punctuation 2011 research report also showed that China's anti-thrombotic drug market scale in 2011 reached 8.135 billion yuan, year-on-year growth of 20.52%, with huge market potential (anti-thrombotic drug market research report: Guangzhou Punctuation (2011)).
The process of human blood coagulation, consisting of an intrinsic pathway, an extrinsic pathway, and a common pathway (Annu. Rev. Med. 2011.62:41-57), is a chain reaction in which the process is continuously enhanced and amplified by sequential activation of multiple zymogens. The coagulation cascade is initiated by the endogenous pathway (also known as the contact activation pathway) and the exogenous pathway (also known as the tissue factor pathway) to produce FXa, which then forms thrombin (FIIa) by a common pathway, and fibrin is finally formed.
The endogenous pathway refers to the process from the activation of factor XII to the formation of XIa-VIIIa-Ca2+P L complex and the activation of factor X, and the exogenous coagulation pathway refers to the process from the release of tissue factor (TF) to the formation of TF-VIIaCa2+ complex and the activation of factor X. The common pathway refers to the process in which after the formation of factor Xa, the two pathways are combined into one, prothrombin is activated, and fibrin is finally formed, and FXI is necessary for maintaining the endogenous pathway and plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin feedback activates FXI, and activated FXI (FXIa) in turn promotes the mass production of thrombin, thereby amplifying the coagulation cascade. Therefore, antagonists of FXI have been extensively developed for the treatment of various thrombi.
Traditional anticoagulant drugs such as warfarin, heparin, low molecular weight heparin (LMWH), and new drugs marketed in recent years, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.,) have a good effect on reducing thrombosis, and occupy the majority of cardiovascular and cerebrovascular market with their remarkable effectiveness, but their side effects are also more and more significant, of which “bleeding risk” is one of the most serious problems (N. Engl. J. Med. 1991; 325: 153-8, Blood. 2003; 101: 4783-4788).
Human FXI deficiency (FXI activity<15 U/dL) is also known as type C hemophilia. This type of patient has a mild bleed phenotype and seldom spontaneous bleeding. Even in the case of injury or surgery, the body's hemostatic function is not affected. Patients with type C hemophilia can be pregnant normally (Arterioscler Thromb. Vasc. Biol. 2010; 30: 388-392). This shows that the safety of FXIa is significantly better than that of FXa. Therefore, the target FXIa has become a hot research topic among major companies and research institutions. In the thrombus model, inhibition of FXIa factor can effectively inhibit thrombus formation, but in the case of more severe thrombosis, FXIa has little effect (Blood. 2010; 116 (19): 3981-3989). Clinical statistics show that increasing the amount of FXIa increases the prevalence of VTE (Blood 2009; 114: 2878-2883), while those with severe FXIa deficiency have a reduced risk of suffering from DVT (Thromb. Haemost. 2011; 105: 269-273).
FXIa is an emerging target, and patents disclosing compounds having FXIa inhibitory activity include WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, and US20050171148. Among them, only Bayer's antisense oligonucleotides (ASO) BAY-2306001 entered the clinical phase II study and achieved good results. In the clinical Phase I trial of the drug, the subject's FXI activity showed a sustained, dose-dependent decrease, accompanied by a prolongation of aPTT, even if the FXI in the body fell to an undetectable level, there would be no drug-related hemorrhagic symptoms. The results show the potential of FXIa as an emerging target (Arterioscler Thromb. Vasc. Biol., 2013, 33(7) 1670-1678). However, FXI ASO is administered by injection and has a slow onset of action. It takes several weeks to form an antithrombotic effect, which may be limited as a preventive drug. In terms of small molecule inhibitors, only FXIa inhibitors (BMS company) entered clinical Phase I in 2014. So far, no clinical results have been reported, therefore, the research of new FXIa inhibitors is of great significance.
The present invention devises a novel small molecule FXIa antagonist having the structure of formula (AI), wherein R1 in the formula is C(O)R7, which has a significant improvement on the anticoagulant effect and pharmacological absorption of the entire compound. The compounds of the present invention have higher activity than the disclosed patented compounds having a similar core structure. In particular, the compound of the present invention exhibits excellent anticoagulant action against human blood, and has good pharmacokinetic activity, and can be used for effectively treating and/or preventing cardiovascular and cerebrovascular diseases and thrombotic symptoms.